1. Field of the Invention
The present invention relates to an agent for the treatment of bone diseases such as traumatic fracture, fatigue fracture, pathologic fracture as well as, for example, reduction in bone strength accompanied by various diseases and inhibition of bone formation accompanied by disease
2. Statement of the Prior Art
For the treatment of traumatic fracture or fatigue fracture, a method is utilized for repositioning (or repositing) and fixing an injured site and then allowing the natural healing ability of the patient to occur. In natural healing of fractured bone, bone union requires a number of days, e.g., about 2 weeks for metacarpal bone, about 5 weeks for forearm bone and about 12 weeks for neck of femur, on the average. In this case, pharmacological treatment is not usually performed but nutritional treatment such as an administration of calcium, is done, if necessary and desired.
Furthermore in pathologic fracture resulting from osteoporosis, diabetes, etc., the natural healing ability of a patient is lowered and hence, in addition to the reposition and fixing of an injured site, pharmacological treatment, an administration of estrogen or calcitonin, etc., is applied; or the above pharmacological treatment is performed in combination with the nutritional treatment. The pharmacological treatments or those in combination with nutritional treatment are also applied to the treatment of reduced bone strength resulting from diseases such as osteoporosis or diabetes.
Under the actual circumstance that fracture treatment has been left to the natural healing-ability of the patient himself, development of an oral agent for accelerating fracture healing comprising 24,25-dihydroxycholecalciferol was recently reported: the agent is useful as a drug for shortening the period of fracture healing (Japanese Patent Application KOKAI No. 63-310828). Reports have been also made on agents for the treatment of bone diseases such as an agent for accelerating bone formation, comprising rentinan (Japanese Patent Application KOKAI No. 63-17828), an agent for the treatment of bone diseases comprising at least one agent selected from the group consisting of chitin, chitosan and derivatives thereof (Japanese Patent Application KOKAI No. 63-156726), as new drugs for shortening a period for fracture healing or improving reduced bone strength accompanied by various diseases; or an agent comprising physiologically active ganglioside of retina, and the like (Japanese Patent Application KOHYO No. 63-502035).
The basic fibroblast growth factor (hereinafter abbreviated as bFGF) is a peptidic cell growth factor which was confirmed to be present in pituitary, brain, retina, corpus luteum, adrenal, kidney, placenta, prostate and thymus. It is known that bFGF induces the proliferation of mesodermal cells including vascular endothelial cells [xe2x80x9cCell Growth Factor Part IIxe2x80x9d, edited by Tissue Culture Association, Japan, pages 15 to 20, published by Asakura Publishing Co.). In recent years, bFGF has been also isolated from cartilage and bone [J.B.C., 260, 2399-2403 (1985); ibid., 261, 12665-12674 (1986)].
It was expected that the bFGF would effectively accelerate the fracture healing, since bFGF evokes a proliferation of mesodermal cells including vascular endothelial cells and is present in cartilage or bone. The in vivo test on bone formation reveals that bFGF accelerates bone formation only in combination with decalcified bovine bone containing a bone growth factor [Act. Orthop. Scand., 60, 473-476 (1989)]. bFGF has a high structural similarity to an acidic fibroblast growth factor which accelerated callus formation in fractured ends at the early stage of fracture healing but inhibited the matrix synthesis of cartilage or bone and was thus evaluated to be inferior to the control group, in bone strength at the site of callus formation [J. Orthopaedic Res., 8, 364-371 (1990)]. bFGF is also recognized to have a high similarity to the acidic fibroblast growth factor in view of the action in vivo.
In the trend of the studies on bFGF as described above, the present inventors have developed drugs for the first time, which can accelerate callus formation at a fracture site by application of bFGF alone, accelerate bone formation for bone defect, promote bone union, improve the strength at a fracture site and increase the bone strength.
The present invention has been made in view of the actual situation of aforementioned treatment for bone diseases, and an object of the present invention is to provide a novel agent for the treatment of bone diseases which can shorten the healing period of various fractures including acceleration of bone formation for bone defects, improve bone strength of fused bones and also improve reduced bone strength accompanied by various diseases.
As a result of extensive investigation to accomplish the aforesaid object, the present inventors have succeeded in developing useful drugs as agents for the treatment of bone diseases using a basic fibroblast growth factor (bFGF) and have come to complete the present invention.
That is, the agent for the treatment of bone diseases of the present invention is characterized by comprising as an effective ingredient a basic fibroblast growth factor (bFGF) and/or an analogue thereof.